Bacteriophage combinations significantly reduce clostridium difficile growthIn vitroand proliferation in vivo

Nale, J. Y., Spencer, J., Hargreaves, K., Buckley, A. B., Trzepiński, P., Douce, G. R. and Clokie, M. (2016) Bacteriophage combinations significantly reduce clostridium difficile growthIn vitroand proliferation in vivo. Antimicrobial Agents and Chemotherapy, 60(2), pp. 968-981. (doi: 10.1128/aac.01774-15) (PMID:26643348) (PMCID:PMC4750681)

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Abstract

The microbiome dysbiosis caused by antibiotic treatment has been associated with both susceptibility to and relapse of Clostridium difficile infection (CDI). Bacteriophage (phage) therapy offers target specificity and dose amplification in situ, but few studies have focused on its use in CDI treatment. This mainly reflects the lack of strictly virulent phages that target this pathogen. While it is widely accepted that temperate phages are unsuitable for therapeutic purposes due to their transduction potential, analysis of seven C. difficile phages confirmed that this impact could be curtailed by the application of multiple phage types. Here, host range analysis of six myoviruses and one siphovirus was conducted on 80 strains representing 21 major epidemic and clinically severe ribotypes. The phages had complementary coverage, lysing 18 and 62 of the ribotypes and strains tested, respectively. Single-phage treatments of ribotype 076, 014/020, and 027 strains showed an initial reduction in the bacterial load followed by the emergence of phage-resistant colonies. However, these colonies remained susceptible to infection with an unrelated phage. In contrast, specific phage combinations caused the complete lysis of C. difficile in vitro and prevented the appearance of resistant/lysogenic clones. Using a hamster model, the oral delivery of optimized phage combinations resulted in reduced C. difficile colonization at 36 h postinfection. Interestingly, free phages were recovered from the bowel at this time. In a challenge model of the disease, phage treatment delayed the onset of symptoms by 33 h compared to the time of onset of symptoms in untreated animals. These data demonstrate the therapeutic potential of phage combinations to treat CDI.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Spencer, Dr Janice and Douce, Dr Gillian and Buckley, Dr Anthony
Authors: Nale, J. Y., Spencer, J., Hargreaves, K., Buckley, A. B., Trzepiński, P., Douce, G. R., and Clokie, M.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Antimicrobial Agents and Chemotherapy
Publisher:American Society for Microbiology
ISSN:0066-4804
ISSN (Online):1098-6596
Copyright Holders:Copyright © 2016 Nale et al.
First Published:First published in Antimicrobial Agents and Chemotherapy 60(2):968-981
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
492111Genetic and phenotypic characterisation of emerging virulent Clostridium difficileGillian DouceWellcome Trust (WELLCOME)086418/B/08/ZIII - BACTERIOLOGY